Substituent Effect on the Structure and Biological Property of 99mTc-Labeled Diphosphonates: Theoretical Studies

Theoretical calculations based on density functional theory (DFT) were performed to study the substituent effect on the geometric and electronic structures as well as the biological behavior of technetium-99m-labeled diphosphonate complexes. Optimized structures of these complexes are surrounded by six ligands in an octahedral environment with three unpaired 4d electrons (d3 state) and the optimized geometry of 99mTc-MDP agrees with experimental data. With the increase of electron-donating substituent or tether between phosphate groups, the energy gap between frontier orbitals increases and the probability of non-radiative deactivation via d-d electron transfer decreases. The charge distribution reflects a significant ligand-to-metal electron donation. Based on the calculated geometric and electronic structures and biologic properties of 99mTc-diphosphonate complexes, several structure-activity relationships (SARs) were established. These results may be instructive for the design and synthesis of novel 99mTc-diphosphonate bone imaging agent and other 99mTc-based radiopharmaceuticals. Key Words: Bone imaging agent, 99mTc-diphosphonate, Substituent effect, SAR, DF